The present invention relates to the delivery of drug esters through an inhalation route. Specifically, it relates to aerosols containing drug esters that are used in inhalation therapy.
There are a number of compounds containing acids and alcohols that are currently marketed as drugs. In certain circumstances, the presence of such functionality prevents effective drug delivery. This phenomenon could be due to a range of effects, including poor solubility and inadequate transcellular transport.
It is desirable to provide a new route of administration for drug acids and alcohols that rapidly produces peak plasma concentrations of the compounds. The provision of such a route is an object of the present invention.
The present invention relates to the delivery of drug esters through an inhalation route. Specifically, it relates to aerosols containing drug esters that are used in inhalation therapy.
In a composition aspect of the present invention, the aerosol comprises particles comprising at least 5 percent by weight of drug ester. Preferably, the drug ester has a decomposition index less than 0.15. More preferably, it has a decomposition index less than 0.10 or 0.05. Preferably, the particles comprise at least 10 percent by weight of drug ester. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97 percent by weight of drug ester.
Typically, the drug ester is an ester of a drug from one of the following classes: antibiotics, anticonvulsants, antidepressants, antihistamines, antiparkisonian drugs, drugs for migraine headaches, drugs for the treatment of alcoholism, muscle relaxants, anxiolytics, nonsteroidal anti-inflammatories, other analgesics and steroids.
Typically, where the drug ester is an ester of an antibiotic, it is selected from an ester of one of the following compounds: cefmetazole; cefazolin; cephalexin; cefoxitin; cephacetrile; cephaloglycin; cephaloridine; cephalosporins, such as cephalosporin c; cephalotin; cephamycins, such as cephamycin a, cephamycin b, and cephamycin c; cepharin; cephradine; ampicillin; amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin; benzylpenicillin; clometocillin; cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin; penicillins, such as penicillin n, penicillin o, penicillin s, and penicillin v; chlorobutin penicillin; dicloxacillin; diphenicillin; heptylpenicillin; and metampicillin.
Typically, where the drug ester is an ester of an anticonvulsant, it is selected from an ester of one of the following compounds: 4-amino-3-hydroxybutyric acid, ethanedisulfonate, gabapentin, and vigabatrin.
Typically, where the drug ester is an ester of an antidepressant, it is selected from an ester of one of the following compounds: tianeptine and S-adenosylmethionine.
Typically, where the drug ester is an ester of an antihistamine, it is an ester of fexofenadine.
Typically, where the drug ester is an ester of an antiparkinsonian drug, it is selected from an ester of one of the following compounds: apomorphine, baclofen, levodopa, carbidopa, and thioctate.
Typically, where the drug ester is an ester of a drug for migraine headaches, it is selected from an ester of one of the following compounds: aspirin, diclofenac, naproxen, tolfenamic acid, and valproate.
Typically, where the drug ester is an ester of a drug for the treatment of alcoholism, it is an ester of acamprosate.
Typically, where the drug ester is an ester of a muscle relaxant, it is an ester of baclofen.
Typically, where the drug ester is an ester of an anxiolytic, it is selected from an ester of one of the following compounds: chlorazepate, calcium N-carboamoylaspartate and chloral betaine.
Typically, where the drug ester is an ester of a nonsteroidal anti-inflammatory, it is selected from an ester of one of the following compounds: aceclofenac, alclofenac, alminoprofen, amfenac, aspirin, benoxaprofen, bermoprofen, bromfenac, bufexamac, butibufen, bucloxate, carprofen, cinchophen, cimetacin, clidanac, clopriac, clometacin, diclofenac, diflunisal, etodolac, fenclozate, fenoprofen, flutiazin, flurbiprofen, ibuprofen, ibufenac, indomethacin, indoprofen, ketoprofen, ketorolac, loxoprofen, meclofenamate, naproxen, oxaprozin, pirprofen, prodolic acid, salsalate, sulindac, tofenamate, and tolmetin.
Typically, where the drug ester is an ester of an other analgesic, it is selected from an ester of one of the following compounds: bumadizon, clometacin, and clonixin.
Typically, where the drug ester is an ester of a steroid, it is selected from an ester of one of the following compounds: betamethasone, chloroprednisone, clocortolone, cortisone, desonide, dexamethasone, desoximetasone, difluprednate, estradiol, fludrocortisone, flumethasone, flunisolide, fluocortolone, fluprednisolone, hydrocortisone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, pregnan-3-alpha-ol-20-one, testosterone, and triamcinolone.
Typically, where the drug ester is an ester of a drug acid, the ester is selected from an ester of the following type: C1-C6 straight chain substituted or unsubstituted alkyl ester, C1-C6 branched chain substituted or unsubstituted alkyl ester, C3-C6 substituted or unsubstituted cyclic alkyl ester, C1-C6 substituted or unsubstituted alkenyl ester, C1-C6 substituted or unsubstituted alkynyl ester, and substituted or unsubstituted aromatic ester.
Typically, where the drug ester is an ester of a drug alcohol, the ester is selected from an ester of the following type: C1-C6 substituted or unsubstituted straight chain alkanoate, C1-C6 substituted or unsubstituted branched chain alkanoate, C1-C6 substituted or unsubstituted alkenoate, and C1-C6 substituted or unsubstituted alkynoate.
Typically, the drug ester is selected from one of the following: ketoprofen methyl ester, ketoprofen ethyl ester, ketoprofen norcholine ester, ketorolac methyl ester, ketorolac ethyl ester, ketorolac norcholine ester, indomethacin methyl ester, indomethacin ethyl ester, indomethacine norcholine ester, and apomorphine diacetate.
Typically, the aerosol has a mass of at least 0.01 mg. Preferably, the aerosol has a mass of at least 0.05 mg. More preferably, the aerosol has a mass of at least 0.10 mg, 0.15 mg, 0.2 g or 0.25 mg.
Typically, the particles comprise less than 10 percent by weight of drug ester degradation products. Preferably, the particles comprise less than 5 percent by weight of drug ester degradation products. More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of drug ester degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, the aerosol has an inhalable aerosol drug ester mass density of between 0.1 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 50 mg/L.
Typically, the aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL or 108 particles/mL.
Typically, the aerosol particles have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter-of the aerosol particles is less than 2. Preferably, the geometric standard deviation is less than 1.9. More preferably, the geometric standard deviation is less than 1.8, 1.7, 1.6 or 1.5.
Typically, the aerosol is formed by heating a composition containing drug ester to form a vapor and subsequently allowing the vapor to condense into an aerosol.
In a method aspect of the present invention, a drug ester is delivered to a mammal through an inhalation route. The method comprises: a) heating a composition, wherein the composition comprises at least 5 percent by weight of drug ester, to form a vapor; and, b) allowing the vapor to cool, thereby forming a condensation aerosol comprising particles, which is inhaled by the mammal. Preferably, the drug ester has a decomposition index less than 0.15. More preferably, it has a decomposition index less than 0.10 or 0.05. Preferably, the composition that is heated comprises at least 10 percent by weight of drug ester. More preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drug ester.
Typically, the drug ester is an ester of a drug from one of the following classes: antibiotics, anticonvulsants, antidepressants, antihistamines, antiparkisonian drugs, drugs for migraine headaches, drugs for the treatment of alcoholism, muscle relaxants, anxiolytics, nonsteroidal anti-inflammatories, other analgesics and steroids.
Typically, where the drug ester is an ester of an antibiotic, it is selected from an ester of one of the following compounds: cefmetazole; cefazolin; cephalexin; cefoxitin; cephacetrile; cephaloglycin; cephaloridine; cephalosporins, such as cephalosporin c; cephalotin; cephamycins, such as cephamycin a, cephamycin b, and cephamycin c; cepharin; cephradine; ampicillin; amoxicillin; hetacillin; carfecillin; carindacillin; carbenicillin; amylpenicillin; azidocillin; benzylpenicillin; clometocillin; cloxacillin; cyclacillin; methicillin; nafcillin; 2-pentenylpenicillin; penicillins, such as penicillin n, penicillin o, penicillin s, and penicillin v; chlorobutin penicillin; dicloxacillin; diphenicillin; heptylpenicillin; and metampicillin.
Typically, where the drug ester is an ester of an anticonvulsant, it is selected from an ester of one of the following compounds: 4-amino-3-hydroxybutyric acid, ethanedisulfonate, gabapentin, and vigabatrin.
Typically, where the drug ester is an ester of an antidepressant, it is selected from an ester of one of the following compounds: tianeptine and S-adenosylmethionine.
Typically, where the drug ester is an ester of an antihistamine, it is an ester of fexofenadine.
Typically, where the drug ester is an ester of an antiparkinsonian drug, it is selected from an ester of one of the following compounds: apomorphine, baclofen, levodopa, carbidopa, and thioctate.
Typically, where the drug ester is an ester of a drug for migraine headaches, it is selected from an ester of one of the following compounds: aspirin, diclofenac, naproxen, tolfenamic acid, and valproate.
Typically, where the drug ester is an ester of a drug for the treatment of alcoholism, it is an ester of acamprosate.
Typically, where the drug ester is an ester of a muscle relaxant, it is an ester of baclofen.
Typically, where the drug ester is an ester of an anxiolytic, it is selected from an ester of one of the following compounds: chlorazepate, calcium N-carboamoylaspartate and chloral betaine.
Typically, where the drug ester is an ester of a nonsteroidal anti-inflammatory, it is selected from an ester of one of the following compounds: aceclofenac, alclofenac, alminoprofen, amfenac, aspirin, benoxaprofen, bermoprofen, bromfenac, bufexamac, butibufen, bucloxate, carprofen, cinchophen, cinmetacin, clidanac, clopriac, clometacin, diclofenac, diflunisal, etodolac, fenclozate, fenoprofen, flutiazin, flurbiprofen, ibuprofen, ibufenac, indomethacin, indoprofen, ketoprofen, ketorolac, loxoprofen, meclofenamate, naproxen, oxaprozin, pirprofen, prodolic acid, salsalate, sulindac, tofenamate, and tolmetin.
Typically, where the drug ester is an ester of an other analgesic, it is selected from an ester of one of the following compounds: bumadizon, clometacin, and clonixin.
Typically, where the drug ester is an ester of a steroid, it is selected from an ester of one of the following compounds: betamethasone, chloroprednisone, clocortolone, cortisone, desonide, dexamethasone, desoximetasone, difluprednate, estradiol, fludrocortisone, flumethasone, flunisolide, fluocortolone, fluprednisolone, hydrocortisone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, pregnan-3-alpha-ol-20-one, testosterone, and triamcinolone.
Typically, where the drug ester is an ester of a drug acid, the ester is selected from an ester of the following type: C1-C6 straight chain substituted or unsubstituted alkyl ester, C1-C6 branched chain substituted or unsubstituted alkyl ester, C3-C6 substituted or unsubstituted cyclic alkyl ester, C1-C6 substituted or unsubstituted alkenyl ester, C1-C6 substituted or unsubstituted alkynyl ester, and substituted or unsubstituted aromatic ester.
Typically, where the drug ester is an ester of a drug alcohol, the ester is selected from an ester of the following type: C1-C6 substituted or unsubstituted straight chain alkanoate, C1-C6 substituted or unsubstituted branched chain alkanoate, C1-C6 substituted or unsubstituted alkenoate, and C1-C6 substituted or unsubstituted alkynoate.
Typically, the drug ester is selected from one of the following: ketoprofen methyl ester, ketoprofen ethyl ester, ketoprofen norcholine ester, ketorolac methyl ester, ketorolac ethyl ester, ketorolac norcholine ester, indomethacin methyl ester, indomethacin ethyl ester, indomethacine norcholine ester, and apomorphine diacetate.
Typically, the particles comprise at least 5 percent by weight of drug ester. Preferably, the particles comprise at least 10 percent by weight of drug ester. More preferably, the particles comprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drug ester.
Typically, the condensation aerosol has a mass of at least 0.01 mg. Preferably, the aerosol has a mass of at least 0.05 mg. More preferably, the aerosol has a mass of at least 0.10 mg, 0.15 mg, 0.2 g or 0.25 mg.
Typically, the particles comprise less than 10 percent by weight of drug ester degradation products. Preferably, the particles comprise less than 5 percent by weight of drug ester degradation products. More preferably, the particles comprise 2.5, 1, 0.5, 0.1 or 0.03 percent by weight of drug ester degradation products.
Typically, the particles comprise less than 90 percent by weight of water. Preferably, the particles comprise less than 80 percent by weight of water. More preferably, the particles comprise less than 70 percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10 percent, or 5 percent by weight of water.
Typically, the particles of the delivered condensation aerosol have a mass median aerodynamic diameter of less than 5 microns. Preferably, the particles have a mass median aerodynamic diameter of less than 3 microns. More preferably, the particles have a mass median aerodynamic diameter of less than 2 or 1 micron(s).
Typically, the geometric standard deviation around the mass median aerodynamic diameter of the aerosol particles is less than 2. Preferably, the geometric standard deviation is less than 1.9. More preferably, the geometric standard deviation is less than 1.8, 1.7, 1.6 or 1.5.
Typically, the delivered aerosol has an inhalable aerosol drug ester mass density of between 0.1 mg/L and 100 mg/L. Preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 75 mg/L. More preferably, the aerosol has an inhalable aerosol drug mass density of between 0.1 mg/L and 50 mg/L.
Typically, the delivered aerosol has an inhalable aerosol particle density greater than 106 particles/mL. Preferably, the aerosol has an inhalable aerosol particle density greater than 107 particles/mL or 108 particles/mL.
Typically, the rate of inhalable aerosol particle formation of the delivered condensation aerosol is greater than 108 particles per second. Preferably, the aerosol is formed at a rate greater than 109 inhalable particles per second. More preferably, the aerosol is formed at a rate greater than 1010 inhalable particles per second.
Typically, the delivered condensation aerosol is formed at a rate greater than 0.5 mg/second. Preferably, the aerosol is formed at a rate greater than 0.75 mg/second. More preferably, the aerosol is formed at a rate greater than 1 mg/second, 1.5 mg/second or 2 mg/second.
Typically, between 0.1 mg and 100 mg of drug ester are delivered to the mammal in a single inspiration. Preferably, between 0.1 mg and 75 mg of drug ester are delivered to the mammal in a single inspiration. More preferably, between 0.1 mg and 50 mg of drug ester are delivered in a single inspiration.
Typically, the delivered condensation aerosol results in a peak plasma concentration of drug acid or drug alcohol in the mammal in less than 1 h. Preferably, the peak plasma concentration is reached in less than 0.5 h. More preferably, the peak plasma concentration is reached in less than 0.2, 0.1, 0.05, 0.02 or 0.01 h.
In a kit aspect of the present invention, a kit for delivering a drug ester through an inhalation route to a mammal is provided which comprises: a) a composition comprising at least 5 percent by weight of drug ester; and, b) a device that forms a drug ester aerosol from the composition, for inhalation by the mammal. Preferably, the composition comprises at least 20 percent, 30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent by weight of drug ester.
Typically the drug ester has a decomposition index less than 0.15. More preferably, it has a decomposition index less than 0.10 or 0.05.
Typically, the device contained in the kit comprises: a) an element for heating the drug ester composition to form a vapor; b) an element allowing the vapor to cool to form an aerosol; and, c) an element permitting the mammal to inhale the aerosol.